The androgen receptor (“AR”) is a type of nuclear receptor which is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone. The main function of the androgen receptor is as a DNA binding transcription factor which regulates gene expression. However the androgen receptor also has additional functions independent of DNA binding. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.
Whilst in humans the AR gene is single copy and found on the X chromosome at position Xq11-12, the receptor itself exists in two iso-forms (A and B). AR-A is an 87 kDa protein which lacks the first 187 amino acids (N-terminal truncation). Isoform AR-B is the full length 110 kDa version.
The binding of an androgen to the androgen receptor induces a conformational change in the receptor, resulting in a dissociation of heat shock proteins, dimerization and transport from the cytosol to the cell nucleus where the androgen receptor dimer binds to specific DNA sequences—referred to as hormone response elements. Depending on the interaction with other nuclear proteins, the AR controls gene expression, either increasing or decreasing transcription of specific genes, such as insulin-like growth factor I (IGF-1).
Androgen receptors can also have cytoplasmic activities through interaction with signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of gene transcription, for example ion transport, as well as indirect influence of gene transcription, for example via mediating other signal transduction pathways, thereby influencing the activity of other transcription factors.
The over-expression of androgen receptor, or expression of mutated androgen receptor genes, has been indicated in several diseases, such as cancer, including prostate cancer and breast cancer, as well as other disorders such as polyglutamate disease (Monks et al., PNAS Nov. 2, 2007, published on line) alopecia, benign prostatic hyperplasia, spinal and muscular atrophy and Kennedy disease.
WO97/11170 describes a method of treating a patient diagnosed as having benign prostatic hyperplasia or a prostate cancer comprising administering an antisense oligonucleotide which selectively hybridises to the androgen receptor mRNA. Three antisense oligonucleotide sequences of between 27-29 nucleotides are disclosed.
U.S. Pat. No. 6,733,776 and EP 0 692 972 describe a method for treating androgenic alopecia by applying liposomes comprising an antisense nucleic acid that hybridises to an androgen receptor gene. No antisense molecules having specific sequences and targeting the androgen receptor are provided.
US 2005/0164970 describes a method of treating prostate cancer using siRNA complexes targeting the androgen receptor mRNA.
WO 2005/027833 describes a method of treating prostate cancer comprising administering to a patient an oligonucleotide comprising between 12-40 morpholino sub-units.
WO 2001/083740 describes an antisense compound having an uncharged morpholino backbone of between 18 to 20 contiguous units which targets the human androgen receptor.
Morpholino antisense compounds work via binding to the nucleic acid target to block access to the mRNA by other molecules, such as molecules involved in mRNA splicing or translation initiation.
U.S. Pat. No. 7,067,256 describes a ribozyme which apparently mediates inactivation of the androgen receptor. A 19-nucleotide RNA antisense molecule targeted to a region of the androgen receptor mRNA is provided.
However, despite the application of siRNA, morpholino-containing antisense oligonucleotides and ribozymes, none of the above androgen receptor inhibitors have been successful in efficiently down-regulating the androgen-receptor in vivo and at pharmacologically acceptable dosages.
The invention provides a new class of androgen receptor antagonists which contain locked nucleic acid (“LNA”) monomers, and are targeted to particularly effective target sites on the androgen receptor mRNA.